This invention relates to a method of magnetic resonance imaging of the human or animal (e.g. mammalian, reptilian or avian) body by which lung function and, if desired, morphology may be investigated.
Lung function is of interest to physicians, especially when dealing with patients who may have abnormalities of ventilation or perfusion or other determinants of gas exchange in the lung. For proper lung function five conditions must be met:
1. gas (air) must be pumped into and out of the lungs;
2. the gas must be distributed evenly within the lungs;
3. gases must be exchanged by diffusion between the blood and the alveolar space;
4. blood must be pumped through the lungs; and
5. the distribution of the blood in the lungs should correspond to the distribution of gas in the alveolar space (i.e. where the gas penetrates to, blood should flow).
All diseases and ailments relating to the lungs and airways affect one or more of the five conditions above.
It has therefore been known to study lung ventilation and perfusion using various diagnostic techniques. The conventional technique is known as VQ imaging and involves the use of two different radiopharmaceuticals, one to study perfusion and the other to study ventilation.
The perfusion agent is generally a particulate (e.g. 99mTc-microaggregated albumin) which is administered intravenously upstream of the lungs and lodges in the precapillary arterioles.
An image of the lungs is recorded with a gamma camera and the signal intensity may be used to detect local abnormalities in blood flow.
The ventilation agent is generally a radioactive gas or aerosol or microparticulate, e.g. 133Xe, 127Xe or 81mKr, or a 99mTc-DTPA aerosol or 99mTc-labelled carbon particles. The agent is inhaled and an image is recorded with a gamma camera. Signal intensity and distribution may be used to detect airway obstructions or regional abnormalities in ventilation.
Where there is a mismatch between the ventilation and perfusion images (which are generated at different times), various different lung malfunctions, diseases or abnormalities may be diagnosed, e.g. pulmonary embolism, pleural effusion/atelectasis, pneumonia, tumour/hilar adenopathy, pulmonary artery atresia or hyperplasia, fibrosing mediastinitis, AVM, CHF, pulmonary artery sarcoma, and intravenous drug use. Heterogenous perfusion patterns may likewise be used to diagnose various disease states or disorders, e.g. CHF, lymphangitic carcinomatosis, non-thrombogenic emboli, vasculitis, chronic interstitial lung disease, and primary pulmonary hypertension. Decreased perfusion to one lung may be used to diagnose pulmonary embolism, pulmonary agenesis, hypoplastic lung (pulmonary artery atresia), Swyer-James syndrome, pneumothorax, massive pleural effusion, tumour, pulmonary artery sarcoma and shunt procedures for congenital heart disease.
VQ imaging however involves exposing the patient to radiation doses from two radiopharmaceuticals in two temporally separate imaging procedures. Clearance of the injected particulate agent is relatively slow and the agent is taken up in other organs besides the lungs. Moreover, in patients with severe pulmonary hypertension, the injected particulate causes a risk of acute right heart failure. For pregnant patients the radiation dose involved in VQ imaging results in undesirable levels of radiation exposure for the foetus.
Furthermore, for most diagnostic purposes mentioned above the resolution of conventional VQ imaging is unsatisfactory.
There is thus a need for a technique which permits lung function to be assessed without the drawbacks associated with VQ imaging.
In magnetic resonance (mr) imaging, radiofrequency signals from non-zero spin nuclei which have a non-equilibrium nuclear spin state distribution are detected and may be manipulated to provide images of the subject under study. In conventional mr imaging the nuclei responsible for the detected signals are protons (usually water protons) and the non-equilibrium spin state distribution is achieved by placing the subject in a strong magnetic field (to enhance the population difference between the proton spin states at equilibrium) and by exposing the subject to pulses of rf radiation at the proton Larmor frequency to excite spin state transitions and create a non-equilibrium spin state distribution. However the maximum deviation from equilibrium is that achievable by spin state population inversion and, since the energy level difference between ground and excited states is small at the temperatures and magnetic field strengths accessible, the signal strength is inherently weak.
An alternative approach that has been developed is to xe2x80x9chyperpolarizexe2x80x9d (i.e. obtain a nuclear spin state population difference greater than the equilibrium population difference) an imaging agent containing non-zero nuclear spin nuclei (e.g. by optical pumping, by polarization transfer or by subjecting such nuclei ex vivo to much higher magnetic fields than those used in the mr imaging apparatus), to administer the hyperpolarized agent to the subject, and to detect the mr signals from the hyperpolarized nuclei as they relax back to equilibrium. In this hyperpolarized mr imaging technique, described for example in WO95/27438, the hyperpolarized material is conveniently in gaseous form, e.g. 3He or 129Xe, and it may thereby be administered by inhalation into the lung and the mr signal detected may be used to generate a morphological image of the lungs.
Since the relaxation time T1 for 3He in the lungs is about 10 seconds it is feasible, using fast imaging techniques, to generate a morphological image of the lungs from the 3He signal following inhalation of hyperpolarized 3He gas and at any desired stage of the breathing cycle, e.g. during breathhold. Since the mr signal selected is from the 3He atoms and since the helium is in the gas phase in the lungs, the image detected is essentially only of the airways into and within the lungs. By administering the hyperpolarized agent as a bolus followed or preceded by other gases or aerosols, e.g. by air, nitrogen or 4He, the hyperpolarized agent can be positioned at any desired section of the airways or other aerated spaced in the body, e.g. it may be flushed from the trachiobronchial tree and the image generated is then essentially only of the alveolar space.
We have now found that functional imaging of the lungs may be carried out effectively using mr imaging of an inhaled hyperpolarized agent by making use of the variation with time of the relaxation rate T1 of the hyperpolarized agent.
Viewed from one aspect therefore, the invention provides a method of detecting regional variations in oxygen uptake from the lungs of an air-breathing animal subject, e.g. a mammalian (human or non-human), avian or reptilian subject, said method comprising administering into the lungs of said subject a diagnostically effective amount of a gaseous hyperpolarized magnetic resonance imaging agent, detecting the magnetic resonance signal from said agent in said lungs, determining the temporal variation in relaxation rate (e.g. T1 relaxation rate) for said signal for at least one region of interest within said lungs, and from said variation generating a qualitative or quantitative value or image indicative of the oxygen concentration in the alveolar space in said at least one region of interest, and if desired the time dependency of such concentration as a result for example of physiological process, e.g. oxygen uptake by perfusion.
In a preferred embodiment, the method of the invention also involves generation of a temporal and/or spatial image of the distribution of the hyperpolarized agent in at least part of the lungs of the subject, preferably in the alveolar space within the lungs.
In a further preferred embodiment, the method also involves generation of a magnetic resonance image of at least part of the lungs of the subject following administration into the subject""s vasculature of a second mr agent, preferably an agent which affects proton relaxation (with the image generated being a proton mr image) or more preferably an agent containing non-proton mr active nuclei (e.g. 19F, 13C, 31P, etc.) in which case the mr image will be generated from mr signals from such non-proton mr active nuclei. The mr active nuclei in the second agent will preferably not be the same as those in the hyperpolarized agent unless the image generated using the second agent is generated at a time when the lungs contain substantially none of the hyperpolarized agent.
Lung volume may also be estimated from the integrated 3He mr signal (or by 3He mrs) following inhalation of the 3He without air, breathhold, and expiration where the expired volume is measured directly and the residual hyperpolarization of the retained 3He is extrapolated from the hyperpolarization value (signal strength) monitored during breathhold.
In the method of the invention, it is preferred that for at least part of the mr signal detection period (preferably at least 1 second, more preferably at least 5 seconds, still more preferably at least 10 seconds, e.g. 20 sec to 1 minute), there be substantially no flow of gas into or out of the lungs, e.g. that there should be a breathhold period, and that the indication of oxygen uptake be derived from mr signals detected during at least part of this period. However, in a preferred embodiment, the method of the invention will also involve mr signal detection during gas flow into and/or out of the lungs with or without a period of breathhold. In this way, spatial or temporal images or other indications of lung ventilation may be generated from the detected mr signals.
Because the detected mr signal derives from the hyperpolarized agent, the signal strength is effectively independent of the primary field strength of the magnet in the mr imager. Accordingly low or high field, e.g. 0.05 to 3.5T, machines may be used.